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TAKAMIZAWA, HIRAI,SATO, AND TORI
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Studies on the Pyrimidine Derivatives. XXIX. Reactions of 3-Ethoxy-2-methoxymethylenepropionitri3e and 3-khoxy -Z-ethoxymethoxymethylpropionitrile with Urea and Thiourea Derivatives lj2
AKIRATAKAMIZAWA, KENTARO HIRAI,YOSHIROSATO,AND KAZUOTORI Shionogi Research Laboratory, Shionogi and Company, Ltd., Osaka, J a p a n Received October 89, 1963
3-Ethoxy-2-methoxymethylenepropionitrile( I ) or its acetal (11) undergo condensation with urea, N-substituted ureas, thiourea, and N-substituted thiourea. The condensation has been carried out by heating the enol ether propionitrile ( I ) or acetal propionitrile (11)in ethanol solution, in the presence of hydrochloric acid, (III), with N,N'-dimethylurea to yield with urea to obtain directly 5-cyan0-2-0~0-1,2,3,4-tetrahydropyrimidine 5-cyano-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine ( I X ) , with N-methylurea to give a mixture of 5cyano-l-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine ( X ) and its isomeric 3-methyl compound ( X I ) , which waa separated into each isomer, and with N-phenylurea to obtain exclusively the 1-phenyl compound (XV). Further dehydrogenation of these compounds made possible a new synthetic route to pyrimidines. The condensation was also carried out with thiourea and I or I1 in alcoholic solution in the presence of hydrochloric acid to obtain 5-cyano-2-0~0-6H-2,3-dihydr0-1,3-thiazine (XVIII) and with N-phenylthiourea to give XVIII and aniline. Elucidation of the structures of these compounds is described.
We have previously reported the reaction of acetamidine3 and related amidines4 with 3-ethoxy-2-methoxymethylenepropionitrile (I) to give 2-substituted 4amino-5-ethoxymethylpyrimidines, and with 3-ethoxy2-e t hox ymet hoxyniet hy lpropionitrile (II) to yield 2,7disubstituted 5,6-dihydropyrimido [4,5-d]pyrimidines.3 , 4 This paper deals with the reaction of I or I1 with urea, N-substituted ureas, thiourea, and N-substituted thiourea (see Scheme I). Reaction of I, a mixture of geometrical isomers,s with urea was carried out in ethanol solution in the presence of hydrochloric acid. The base-catalyzed condensation of aldehyde nitrile derivatives with urea is a standard synthesis of cytosine derivatives.6 However, in this case a product 111, C6H5N30,was obtained in 42.6% yield by acid-catalyzed reaction, and no evidence for the formation of other products was shown by thinlayer chromatography of the filtrate. The infrared spectrum of I11 shows N H bands, a conjugated C=N band, and an amide I band. Hydrolysis of I11 in concentrated hydrochloric acid gave the amide IV. Acetylation with acetic anhydride afforded the diacetate V. The proton magnetic resonance spectrum' of V (Table I) shows two singlet signals (3H) at 7 7.32 and 7.40 arising from the protons of 1- and 3-N-acetyl groups, respectively. The signals of the protons of C-4 methylene and C-6 methylidyne groups appear at T 5.56 (2H) and 2.05 ( l H ) , respectively; the former is split into a doublet and the latter into a triplet due to the spin coupling ( J = 1.0 c.P.s.) with each other. These results indicate that I11 can be formulated as 5cyano-2-oxo-1,2,3,4-tetrahydropyrimidine. By the action of bromine in acetic acid solution, I11 was dehy(1) A p a r t of this paper has been delivered a t the 19th congress of I.C. P.A.C., London, July 10-17, 1963. ( 2 ) P a r t X X V I I I : C h e m . Pharm. Bull. (Tokyo), 12, 398 (1964). (3) A . Takamizawa, K . I k a w a , and K. Tori, Y a k u g a k u Zasshi, 78, 647 (1958); A . Takamisawa, K. T o k u y a m a , and K. Tori, Bull. C h e m . SOC.J a p a n , 32, 188 ( i g t w . (4) A. Takamizawa and K. Hirai, C h e m . P h a r m . Bull. (Tokyo), 12, 393 (1964). ( 5 ) A. Takamizawa, K. Hirai, a n d K. Tori, ibid., 11, 1212 (1963). (6) D. J. Brown, "The Pyrimidines," John Wiley and Sons, Inc., New Yorl:. N. Y . . 1962. pp. 59-61, ( 7 ) A11 the n.m.r. spectra were taken with a Varian A-60 spectrometer on about 10% solution in deuteriochloroform containing about 1 % tetramethylsilane ( T M S ) a8 a n internal reference. Chemical shifts are expressed in 7-values a n d coupling constants are in c.p.8. Accuracy limits are about 7 ~ t 0 . 0 2for chemical shifts a n d a b o u t * 0 . 3 c.p.8. for coupling constants.
drogenated to give 5-cyano-2-0~0-1,2-dihydropyrimidine (VI), which was converted into 5-cyano-2-chloropyrimidine (VII) on treatment with phosphorus oxychloride. Amination of VI1 gave the 2-amino derivative VIII. This compound VI11 was identified as 2amino-5-cyanopyrimidine by comparison of its infrared and ultraviolet spectra with those of an authentic sample.8 Thus the structure of I11 was established. It should be noted that this synthesis is useful in obtaining 2-substituted 5-cyanopyrimidines. Reaction of I with T\;,N'-dimethylurea in ethanol solution in the presence of hydrochloric acid gave a product I X , C7H9N30,in 56.3% yield. Infrared spectrum of IX shows a conjugated C=N band and C=O band, but no nTH band is shown. The n.m.r. spectrum of IX exhibits the signals of the protons of two Smethyl, C-4 methylene, and C-6 methylidyne groups as shown in Table I. Thus IX is formulated as 5-cyano1,3-dimethyl-2-oxo- 1,2,3,4-tetrahydropyrimidine. Reaction of I with N-methylurea in ethanol solution in the presence of hydrochloric acid afforded a product of m.p. 187-188', CsH7N30, which showed two spots on a thin-layer chromatogram and which could be converted into a mixture of acetates. The n.m.r. spectrum of this mixture of acetates consists of four pairs of signals of N-acetyl, N-methyl, C-4 methylene, and C-6 methylidyne protons whose respective relative integrated intensities are about 3:2. Thus, this product was revealed to be a mixture of 3-acetyl-5-cyano-lmethy1-2-0~0-1,2,3,4-tetrahydropyrimidine (XII) and the 3-methyl isomer XI11 in a ratio of 3:2. Thismixture was subjected to column chromatography on alumina and two crystalline products of m.p. 94' (XII) and m.p. 118' (XIII) were obtained separately. The assignment of the structures of these compounds was made as follows. The n.m.r. spectrum of N,N'diacetyl compound V shows the signals of C-4 methylene and C-6 methylidyne protons at lower fields than those of the protons of X,Y'-dimethyl compound I X (see Table I). Therefore, in XI1 and XI11 these protons resonating a t lower fields will be situated a t positions adjacent to the S-acetyl group. The spectrum of XI1 shows the signals of the ?;-acetyl and C-6 (8) J. P . English, J. H . Clark. R . G . Shepard, H. W. Marson, J. Krapcho, a n d R . 0. Roblin, J r . , J . A m . C h e m . SOC.,68, 1039 (1946). (9) T.1.c.: alumina plate, ethyl acetate solvent, detected by iodine vapor.
JULY,1964
STUDIES ON
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PYRIMIDINE DERIVATIVES. XXIX
SCHEME I
1741
oxopyrimidines. The dehydrogenation of X and XI was made separately to yield the same product XIV. N-Phenylurea reacted with I in ethanol solution in the presence of hydrochloric acid to give the product XV, CllHgK;30, in 42.6% yield. The n.m.r. spectrum of the acetate of XV shows that this product is not a mixture and that the acetate XVI can be formulated CN T 2 C N I T C N 3-acetyl-5-cyano-2-oxo-1-phenyl-1,2,3,4-tetrahydroas + N c1 pyrimidine. In this reaction the 3-phenyl isomer was O H VI1 not obtained. I11 VI I Reaction of I with thiourea was also carried out in ethanol solution in the presence of hydrochloric acid ,c=o HiN and the product XVIII, CbH4NzOS, and ammonium chloride were obtained. This product XVIII was hyCzHsOCHzCCN CzHsOCHzCHCN NH2 drolyzed in concentrated hydrochloric acid to give the II I VI11 CHOCHs ,CH amide X X I which was converted into the original XVIII by the action of phosphorus oxychloride. Acetylation of XVIII gave monoacetate X X . These facts suggest that this compound XVIII is 5-cyano-2-oxo6H-2,3-dihydro-lj3-thiazine or its isomeric structure X I X . The n.ni.r. spectrum of X X shows a singlet (3H) a t r 7.38 due to the X-acetyl group, a doublet (2H, J = 0.8 c.P.s.) at r 6.23 due to the C-6 methylene protons, and a triplet ( l H , J = 0.8 c.P.s.) a t r 2.07 due to the C-4 methylidyne proton. The spectrum of XVIII shows a doublet ( J = 0.8 c.P.s.) at T 6.26, and a doubling triplet ( J = 6.5, 0.8 c.P.s.) at r 3.11, which changes into a triplet by the addition of a small amount I 1 1 , A of deuterium oxide to the solution examined. These facts imply that the NH group is situated at a position adjacent to the C-4 niethylidyne group. From all of these observations, XVIII was elucidated Simito be 5-cyano-2-oxo-6H-2,3-dihydro-l,3-t~hiazine. larly, the reaction of I with N-phenylthiourea in ethanol solution in the presence of hydrochloric acid gave XVIII and aniline hydrochloride. These products would result from hydrolysis of the probable 2imino intermediate. In a previous paper,]* acid treatment of the enol ether nitrile I in ethanol was reported to give its acetal 11. In the present cases, it is reasonable to assume that I1 is an intermediate in the reaction of I with ureas or thioureas in ethanol in the presence of hydrochloric acid. This assumption was supported by the facts that I1 reacted with urea, X,S'-diniethylurea, and thiourea to afford 111, IX, and XVIII in 46.7, 56.3, and 24.3% yield, respectively. However, the possibility that a part of the nitrile I can directly react with these reagents to give products analogous to those obtained from the reaction with amidines cannot be excluded at niethylidyne protons at higher fields and those of the this point. K-methyl and C-4 methylene pretons a t lower fields It should be noted that the cyano group in I or I1 did than does that of X I I I . Accordingly, the C-4 methylnot participate in the cyclization reaction with urea, in ene in XI1 should be situated at a position adjacent to contrast to reaction with a m i d i n e ~ . ~Of much interest to the N-acetyl group. Therefore, XI1 can be formuis the fact that the sulfur atom participated preferenlated as 3-acetyl-5-cyano-l-methyl-2-oxo-1,2,3,4-tetratially, probably in a thiol form, in the cyclization reaction hydropyrimidine. Conversely, XI11 can be formulated as the 3-methyl isomer. Hydrolyses of XI1 and (10) This decoupling results from the proton exchanging of t h e K-H [refer to H . M. Fales and A . T . Robertson, Tetrahedron Letters. No.3 , XI11 gave 5-cyano-l-methyl-2-oxo-l,2,3,4-tetrahydro- group 111 (196211. pyrimidine (X) and the 3-methyl isomer X I , respec(11) Spin coupling between -CH and -CONH- protons has frequently been reported [ H . S.Gutowsky and C . H . Holm, J . Chem. Phus.. as, 1228 tively. A mixture of X and XI was dehydrogenated by (1959); G. V. D. Tiers and F. A. Bovey. J . Phus. Chem., 63,302 (19.57); K. the action of 2,3-dichloro-5,6-dicyano-1,4-benzoqui- Tori, A n n . Rept. Shionogz Res. Lab., 1 8 , 114 (19R2): a n d K . Tori and K. none (DDQ) in dioxane solution to give 5-cyano-lKuriyama, Chem. I n d . ( L o n d o n ) , 1525 (1963)). However, i t is of considerable interest to note t h a t = C H proton appreciably couples with a niethyl-2-0~0-1,2-dihydropyrimidine(XIV) in good C O N H proton. yield. It should be noted that this synthesis is a use(12) A . T a k a m i a a n a . K. I k a w a , and M. Xarisada, Yakuoaku Zasphz, 1 8 , ful method for obtaining new ?\'-substituted 5-cyano-2637 (1958).
\
7
+
grCN
TAKAMIZAWA, HIRAI,SATO,AND TORI
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VOL. 29
TABLE I N.M.R.SPECTRAL DATAIN DEUTERIOCHLOROFORM (10%)" Compound
R V, R = R ' = COCHS IX, R R ' = CH3 X, R = CHI; R' = H XI, R = H ; R ' = CH3 X I I , R = CH3; R ' = COCHj XIII, R = COCH3; R' = CHI XVI, R = CeH6; R ' COCHs
N-1-CHs
N-3-CHs
6.87 6.88
7.07
Chemical shift-------T-() N-1-COCHs N-3-COCHs
7.32
7.40
7.08 6.77
7.46 6.97
7.37 7.42
C-4-Hb
5.56 (d) 5.93 (d) 5.87 (d) 5.95 (d) 5.57 ( d ) 5 . 9 2(d) 5.43 (d)
C-6-Hb
2.05 (t) 3.17 (t) 3.20 (t) 3.15 ( m ) 3.08 (t) 2.07 (t) 2.95 ( t )
R XVIII,c R = H 3.11 (d-t) 6.26 (d) XX, R = COCH, 7.38 2.07 (t) 6.23 (d) a Peak multiplicities are represented by d (doublet), t (triplet), m (multiplet), and d-t (doubling triplet). All methyl peaks are sharp singlet,s. J 4 , 6 = 1.0 c.p.5. Observed on a saturated solution.
ofthioureas with I or 11, and the expected product,6 4amin0-5-ethoxymethyl-2-mercaptopyrimidine,was not obtained.
Experimental 5-Cyano-2-oxo-I ,2,3,4-tetrahydropyrimidine (111). A.-3Ethoxy-2-methoxymethylenepropionitrile (I, 2.8 g.) and 1.2 g. of urea were added to a solution of 200 ml. of ethanol and 4 ml. of concentrated hydrochloric acid. The mixture was refluxed for 15 hr. and the product was collected after cooling, yielding 1.35 g. Recrystallization from water afforded 1.05 g. (42.6%) of colorless prisms, m.p. >300", insoluble or slightly soluble in ether, ethyl acetate, chloroform, acetone, and ethanol; infrared spectrum (Nujol mull), 3250, 3100 ( N H ) , 2230 (C+iN), and 1670 cm.? 276 mp. (amide I ) ; ultraviolet spectrum, A:? Anal. Calcd. for C6HsN30: C, 48.77; H , 4.10; N, 34.14. Found: C, 48.76; H, 4.41; N,34.12. B.-A solution of 1.2 g. of urea, 3.8 g. of 11, and 4 ml. of concentrated hydrochloric acid in 200 ml. of ethanol was refluxed for 19 hr. as described above. The product (1.55 9.) was recrystallized from water to afford 1.15 g. (46.7%) of 111. 5-Carboxamido-2-0~0-1,2,3,4-tetrahydropyrimidine (IV).-One gram of I11 was dissolved in 20 ml. of concentrated hydrochloric acid with slight warming and allowed to stand overnight at room temperature. The product was collected and recrystallized from water to afford 0.7 g. (61.1%)of colorless needles, m.p. 286-289" dec.; infrared spectrum shows no C-N band; ultraviolet spec240 mp (log E 4.38), 276 mp (log e 4.38). trum, Anal. Calcd. for C5H7N302: C, 42.56; H, 5.00; N,.29.78. Found: C, 42.47; H, 5.03; Y, 29.82. 5-Cyano-~,3-diacetyl-2-oxo-l,2,3,4-tetrahydropyrimidine (V). -A mixture of 0.5 g. of I11 and 5 ml. of acetic anhydride was refluxed for 8 hr. The excess reagent was removed under reduced pressure and the residue was solidified on trituration with petroleum ether. Recrystallization from a mixture of ether and petroleum ether afforded 0.5 g. (61.4%) of colorless needles, m.p. 7981': infrared soectrum shows no NH band; ultraviolet spectrum, 235 mp (log e 4.11). Anal. Calcd. for CQHONQO,: C. 52.17; H . 4.36; N , 20.28. Found: C , 52.61; H , 4.56; "N: 19.23. 5-Cyano-2-oxo-1,Z-dihydropyrimidine (VI).-A mixture of 0.5 g. of I11 and 10 ml. of glacial acetic acid was heated and a solution of 0.65 g. of bromine in 2 ml. of glacial acetic acid was added to the mixture. The solution was refluxed for 3 hr., the product was collected and recrystallized from ethanol t o afford 0.4 g. (80.3%) of colorless prisms, m.p. 26&262'; ultraviolet spectrum,": :A 257 mp (log e 4.40), 300 mp (shoulder, log e 2 97). LI"8Denn'on
Anal. Calcd. for CsH3N30: C , 49.59; H , 2.50; N , 34.70. Found: C,49.33; H , 2.69; N, 33.93. 2-Chloro-5-cyanopyrimidine (VII).-A mixture of 0.4 g. of VI, 4 ml. of phosphorus oxychloride, and 0.2 ml. of dimethylaniline was refluxed for 1 hr. The excess reagent was removed under reduced pressure, ice-water was added to the residue, and the mixture was extracted with ether. The ethereal extract was dried over anhydrous magnesium sulfate, the ether was removed, and the residue was recrystallized from a mixture of benzene and petroleum ether (b.p. 30-60") to afford 0.3 g. (65.2~o)E;\pale 228 yellow needles, m.p. 130-132"; ultraviolet spectrum, A,, mp (log e 4.10), 260 mp (log e 3.39). Anal. Calcd. for CjH2N3C1: C, 43.05; H , 1.45; N , 30.17; C1,25.42. Found: C,43.35; H , 1.81; N,30.38; C1,25.44. 2-Amino-5-cyanopyrimidine (VIII).-A suspension of 0.5 g. of VI1 in 40 ml. of ethanol saturated with NHI was heated a t 100" for 2 hr. On cooling, the product was collected and recrystallized from ethanol to afford 0.3 g. (69.77,) of colorless prisms, d.p. ca. 260°, lit.* d.p. 30&310"; infrared spectrum (Nujol mull), 3100, 2220, 1677, 1597, 1525, 1385, 1235, 1070, 969, 803, and 659 cm.-'; ultraviolet spectrum,; : A 257 mp (log e 4.46), 296 mp (log e 3.54). Anal. Calcd. for C5H1N4: C , 50.00; H , 3.36; N, 46.65. Found: C, 50.08; H , 3.49; N , 46.09. The infrared and ultraviolet spectra were identical with those of an authentic sample prepared by the method of English, et al.,* from 2-aminopyrimidine by bromination and subsequent cyanation. 5-Cyano- 1,J-dimethyl-2-oxo- 1,2,3,4-tetrahydropyrimidine(1x1. A.-A solution of 0.88 g. of N,N'-dimethylurea, 1.4 g. of I , and 2 ml. of concentrated hydrochloric acid in 100 ml. of ethanol was refluxed for 12 hr. The solution was concentrated in vacuo, neutralized with sodium bicarbonate solution, and extracted with chloroform. The chloroform extract, after drying over anhydrous magnesium sulfate, was evaporated to give the product which on recrystallization from a mixture of benzene and petroleum ether gave 0.85 g. (56.3%) of colorless pillars, m.p. 109"; infrared spectrum (Nujol mull), 2220 em.-' ( C c N ) and no NH band; ultraviolet spectrum, 219 mp (log e 3.93). 290 mp (log e 3.92). Anal. Calcd. for C,H9N30: C, 55.61; H , 6.00; N , 27.80. Found: C , 55.36; H , 6.16; N, 27.60. B.-The solution of 0.88 g. of N,N'-dimethylurea, 1.9 g. of 11, and 2 ml. of concentrated hydrochloric acid in 100 ml. of ethanol was refluxed for 6 hr. as described above and 0.85 g. (56.3%) of I X was obtained. Reaction of I and N-Methy1urea.-A solution of 2.82 g. of I , 1.48 g. of N-methylurea, and 2 ml. of concentrated hydrochloric acid in 100 ml. of ethanol was refluxed for 12 hr. It then was con-
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PYRIMIDINE DERIVATIVES. XXIX
centrated in vacuo, water was added to the residue, and the product was collected, yielding 1.6 g. (54.5%). Recrystallization from ethanol gave 1.25 g. (42.57,) of colorless prisms, m.p. 187-189"; t.l.c., Xi 0.33, 0.26. Anal. Calcd. for C6H,?\j30: C, 52.54; H , 5.15; N, 30.64. Found: C, 52.67; H , 5.41; N,30.35. 3-Acetyl-5-cyano-I-methyl-2-oxo-I ,2,3,4-tetrahydropyrimidine (XII) and I-Acetyl-5-cyano-3-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine (XIII) .-A mixture of 4.5 g. of the product obtained above and 45 ml. of acetic anhydride was refluxed for 5 hr. After removing excess reagent, the residue was recrystallized from a mixture of benzene and petroleum ether to give 4.66 g. (85.07,) of colorless prisms, m.p. 75-78". Anal. Calcd. for C8H9N302:C, 53.62; H , 5.06; N, 23.45. Found: C, 53.88; H , 5.2.5; pu', 22.95. This product (2.4 g.) was chromatographed on alumina. Chloroform eluates yielded 1.O g. of a compound, m.p. 205-206", which was acetylated again with 10 ml. of acetic anhydride to give 1.0 g. of colorless needles, m.p. 94" (recrystallized from a mixture of benzene and petroleum et,her); n.m.r. spectrum (Table I) shows that these crystals are X I I . Ethanol elution yielded 0.4 g. of the product,, m.p. 182-183", whichwasacetylated again with 4 ml. of acetic anhydride to give 0.4 g. of colorless needles, m.p. 118" (recrystallized from a mixture of benzene and petroleum ether); n.m.r. spectrum (Table I) shows that these crystals are XIII. 5-Cyano-I-methyl-2-oxo-I ,2,3,4-tetrahydropyrimidine(X) .A mixture of 0.6 g. of XI1 and 6 ml. of 57, potassium hydroxideethanol was allowed to stand overnight' a t room temperature. The solution was concentrated in vacuo, water was added to the residue, and the product was collected and recrystallized from ethanol to give 0.35 g. of colorless pillars, m.p. 205-206"; t.l.c., Xi 0.33; ultraviolet spectrum,": :A 213 mp (log e 3.92), 286 mp (log e 3.97). Anal. Found: C , 52.21; H , 5.46; N, 30.64. 5-Cyano-3-methyl-2-0~0-1,2,3,4-tetrahydropyrimidine (XI) .A mixture of 0.4 g. of XI11 and 4 ml. of 57, potassium hydroxide and 4 ml. of ethanol was allowed to stand overnight at, room temperature, and concentrated in vacuo. Water was added to the residue and the product was recrystallized from ethanol to give 0.15 g. of colorless rhombics, m.p. 182-183'; t.l.c., Ri 0.25; ultraviolet spectrum, 217 mp (log e 3.96), 278.5 mp (log e 3.90) . Anal. Found: C,52.64; H , 5.37; S , 3 0 . 2 8 . 5-Cyano-l-methyl-2-0~0-1,2-dihydropyrimidine (XIV) . A .A solution of 0.757 g. of DDQ in 10 ml. of dioxane was added to the solution of 0.457 g. of the mixture of X and X I in 10 ml. of dioxane and refluxed for 1 hr. The separated crystals were filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from a mixt,ure of methanol and ethyl acetate to give 0.216 g. of colorless prisms, m.p. 233-234"; the filtrate was concentrated and the residue was purified by alumina chromatography to afford 0.08 g. of the crystals. Both crystals were found to be identical by infrared spectra; t.l.c., Rr 0.15; ultraviolet spectrum, 262 mp (log e4.04), 312 mp (log e 2.75); infrared spectrum (Kujol mull), 2255 (CEN), 1670-1680 em.-' (C=O, C=N), no PU'H band. Anal. Calcd. for C6HsN30: C, 53.33; H , 3.73; N, 31.10. Found: C, 53.02; H, 3.91; N, 30.82. B.-A solution of 0.137 g. of X and 0.227 g. of DDQ in 6 ml. of dioxane was refluxed for 1 hr. as described above and 0.106 g. (78.57,) of XIV was obtained. C.-A solution of 0.044 g. of XI and 0.073 g. of DDQ in 6 ml. of dioxanewas refluxed for 1 hr. as above, and 0.03 g. (69.2%) of XIV was obtained. 5-Cyano-2-oxo-l-phenyl-l,2,3,4-tetrahydropyrimidine(XV).A solution of 5 g. of I , 4.8 g. of N-phenylurea, and 14 ml. of concentrat.ed hydrochloric acid in 37 ml. of ethanol was refluxed for 5 hr. The product was collected, washed with water, and dried, yielding 4.2 g. (607c), m.p. 218-221' dec. Recrystallization from methanol gave 3.0 g. (42.6y0) of colorless prisms, m.p. 220-221' dec.; ultraviolet spectrum, 286.5 mp (log e 4.01).
1743
Anal. Calcd. for CllH9?\j30: C, 66.32; H , 4.56; Y , 21.10. Found: C, 66.18; H , 4.74; N, 20.57. 3-Acetyl-5-cyano-2-oxo-l-phgnyl1,2,3,4-tetrahydropyrimidine (XVI).-A mixture of 0.6 g. of XV and 6 ml. of acetic anhydride was refluxed for 7 hr. After removing excess reagent, the residue was recrystallized from a mixture of benzene and petroleum ether to afford 0.7 g. (96.3y0) of colorless needles, m.p. 160-163'; " : :A 283 mp (log e 3.99). ultraviolet spectrum, Anal. Calcd. for C13H1,X302:C, 64.72; H, 4.60; N, 17.43. Found: C, 64.71; H,4.72; N, 17.04. 5-Cyan0-2-0~0-2,3-dihydrodH-l ,J-thiazine (XVIII) . A.A solution of 7 g. of thiourea, 13.2 g. of I, and 35 ml. of concentrated hydrochloric acid in 700 ml. of ethanol was refluxed for 25 hr. After concentration, chloroform was added to the residue and separated ammonium chloride was filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residual solid was treated with charcoal and recrystallized from water to afford 4.1 g. (31.8%) of colorless pilla'rs, m.p. 120-122'; infrared spectrum (Nujol mull), 3220 ( N H ) , 2220 ( C z N ) , 1680 and 1630 cm.? (amide I and conjugated C=C); ultraviolet spectrum, X",t,"," 241 mp (log e 3.75), 285 mp (log e 3.74) ; t.l.c, Ri 0.51. Anal. Calcd. for CsHaN20S: C, 42.85; H , 2.85; N, 20.00; S, 22.86. Found: C, 43.03; H , 2.98; N, 19.89; S, 23.04. B.-A solution of 1.52 g. of thiourea, 3.8 g. of 11, and 4 ml. of concentrated hydrochloric acid in 200 ml. of ethanol was refluxed for 22 hr., and treated as described above to afford 0.684 g. (24.67,) of XVIII. 5-Carboxamido-2-0~0-2,3-dihydro-6H1,3-thiazine (XXI) .-To 20 ml. of concentrated hydrochloric acid, 0.4 g. of XVIII was added and allowed to stand overnight a t room temperature. Crystals were collected and recrystallized from ethanol to give 0.25 g. (55.5%) of colorless needles, m.p. 205" dec.; infrared spectrum, no C=N band. Anal. Calcd. for Cs&N&S: C, 37.98; H , 3.83; N , 17.72. Found; C, 38.33; H , 3.99; N, 17.79. A mixture of 0.2 g. of XXI and 1.5 ml. of phosphorus oxychloride was refluxed for 1 hr. After evaporation of the reagent under reduced pressure, ice-water was added to the residue and the product was collected. Recrystallization from a mixture of ethyl acetate and petroleum ether gave 0.1 g. of XVIII. 3-Acetyl-5-cyano-2-oxo-2,3-dihydro-6H-l,3-thiazine (XX) .A mixture of 0.1 g. of XVIII and 2 ml. of acetic anhydride was refluxed for 6 hr. After evaporation, the residue was recrystallized from a mixture of benzene and petroleum ether to afford 0.11 g. (84.77,) of colorless needles, m.p. 107-108"; infrared spectrum, no N H band; ultraviolet spectrum, 233 mp (log e 4.09). Anal. Calcd. for C7H~xjzO&: C, 46.16; H , 3.32; N , 15.38. Found: C,46.18; H,3.55; N, 15.38. Reaction of I with N-Phenylthiourea.-A solution of 1.4 g. of I , 1.5 g. of N-phenylthiourea, and 2 ml. of concentrated hydrochloric acid in 100 ml. of ethanol was refluxed for 12 hr. and evaporated in uacuo. Chloroform was added to the residue and aniline hydrochloride (0.4 g., 44.4%) was filtered off. The filtrate was evaporated and the residue was treated with charcoal, and recrystallized from water to afford 0.3 g. (21.4%) of XVIII.
Acknowledgment.-The authors express their deep gratitude to Professors -1. Tomitn arid S. Uyeo of Kyoto University and to Dr. K. Takeda, Director of this laboratory, for their encouragement', and to Professor S.Nagaltura, University of Tokyo, for his helpful discussion. Thanks are due also t,o the members of physicochemical section of this laboratory for infrared and ultraviolet spectral measurements, to the members of the analytical section of this laboratory for elemental analyses, and to Messrs. T. Ishibn and K. Aono for their technical assistance.
